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Friday, September 16, 2011

A clinical trial of chondroitin sulfate for osteoarthritis of the hand reported modest improvements in pain and functionality, compared with placebo. However, realizing full benefits of active therapy required 6 months and there were no clinically important gains in morning stiffness or grip strength. While certain questions remain unanswered, it seems doubtful that chondroitin is a viable alternative therapy for most patients with arthritic hand pain.

Patients were randomized to receive either 800 mg chondroitin sulfate (N=80) or placebo (N=82) once per day for 6 months and were analyzed in an intent-to-treat (ITT) approach. For rescue medication, subjects were allowed to take acetaminophen (500 mg) up to a maximum of 4 g/day; NSAIDs or glucocorticoid agents were not allowed during the study.

Results indicated that, compared with placebo, chondroitin therapy produced statistically significant decreases in global hand pain (8.7 mm VAS reduction, P=0.02) and improvements in hand function (2.14 reduction on FIHOA, P=0.008). In the chondroitin group there also were slight but statistically significant improvements in morning stiffness and in global impression of treatment efficacy as rated by investigators. Improvements in grip strength over time and acetaminophen consumption did not differ between groups (mean≈2 tablets/week in each group), and both chondroitin and placebo had similarly favorable safety profiles.

Based on their findings, the researchers concluded that chondroitin sulfate improves both pain and functionality in patients with symptomatic hand OA, with a good safety profile. However, there were certain aspects of this study and its results suggesting that clinical benefits actually may be only marginal.

COMMENTARY: OA of the hand is a common disorder afflicting up to 30% of adults, according to some sources, and the incidence may increase to 50% or greater in persons over the age of 60 years. Management of this disorder has largely been extrapolated from approaches found useful in treating other forms of OA.

We have previously discussed chondroitin in UPDATES [here] and [here]. It has been found, at best, to be of only minor benefit for arthritis of the knee, hip, or back. A prior meta-analysis of chondroitin for hip and knee arthritis by Wandel et al. [abstract here] discovered only slight improvements of about 3 mm on a 100 mm VAS; far below the 9 mm minimum reductions considered by those researchers to be of clinical importance. Those authors concluded rather strongly that, “Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged.”

Guidelines on the management of hand arthritis from the European League Against Rheumatism (EULAR) [access here] note that chondroitin sulfate is no better than placebo or an NSAID (eg, naproxen) alone for relieving pain or preventing joint erosion. Chondroitin sulfate (and a variation, chondroitin polysulfate) are members of a class called SYSADOA, or Symptomatic Slow Acting Drugs for Osteoarthritis, which also includes glucosamine, avocado-soybean unsaponifiables (ASU), diacerein, and intraarticular hyaluronan (hyaluronic acid). All of these are noted by EULAR to have low toxicity but produce only small beneficial effect sizes, suitable patients for the therapies are not well defined, and clinically relevant joint-structure modification or pharmacoeconomic advantages have not been established.

Subjects in this present study had only moderate hand pain at the outset (VAS=40 mm); although, the researchers described this as being severe. The mean VAS improvement at 6 months of 8.7 mm (95% CI, 1.6 to 15 mm) only marginally approached the 9 mm minimum specified by Wandel et al. (referenced above), and the effect size for this was small (Cohen’s d=0.35). Similarly, the change in functionality score, FIHOA reduction of 2.14 (95% CI 0.6 to 3.7) points, represented only a small-to-medium effect size (d=0.43). [Confidence intervals and effect sizes were calculated by us and not provided in the authors’ text. Also, see prior UPDATE discussing how to determine effect sizes here]

It also is interesting to note that significant differences in pain and functionality scores did not begin to emerge until after at least 3 months of therapy — true to the slow-acting nature of SYSADOA agents. And, while the overall safety profile of chondroitin was judged as favorable, it could be important that there were 138 adverse events (AEs) reported by 68 patients during the trial, equally distributed among chondroitin and placebo groups. Although no seriously harmful events were reported, there was a predominance of gastrointestinal AEs — diarrhea, dyspepsia, nausea, abdominal pain, constipation — in both groups. This is puzzling, unless both active and placebo tablets contained physiologically deleterious ingredients.

Furthermore, the highly purified chondroitin sulfate agent used by Gabay and colleagues in their study is licensed as a prescription drug (Chondrosulf®) in Europe by the Swiss company IBSA, which also sponsored this clinical trial; so, commercial bias must be considered. Chondroitin sulfate is marketed in the United States and many other countries as an unregulated nutraceutical supplement, sold over-the-counter and usually paired with glucosamine. Finding chondroitin sulfate as a sole ingredient can be difficult and the cost, according to one source, is about $84 to $120 (USD) for a 6-month’s 800 mg/day supply (uncompensated by insurance).

The authors claim that the beneficial effects noted for chondroitin sulfate in their study are comparable to those with therapeutic alternatives, such as NSAIDs, and the latter can have significant long-term toxicities. However, there have not been head-to-head comparisons of chondroitin (or other SYSADOA agents) and NSAIDs for hand OA that we know of, and whether chondroitin actually might be a preferred choice for most patients with this condition, or even as supplemental therapy, seems doubtful in view of available evidence.

Several questions remain unanswered. Would chondroitin provide greater relief for patients with more severe hand OA (eg, baseline VAS ≥ 60 mm)? Would improvements in pain and functionality continue or possibly increase beyond 6 months of therapy? Would a combination of chondroitin and glucosamine be more advantageous?

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